Prevent Tumor Progression Research Articles

The structural conformation of the tachykinin domain drives the anti-tumoural activity of an octopus peptide in melanoma BRAFV600E.

Over past decades, targeted therapies and immunotherapy have improved survival and reduced the morbidity of patients with BRAF-mutated melanoma. However, drug resistance and relapse hinder overall success. Therefore, there is an urgent need for novel compounds with therapeutic efficacy against BRAF-melanoma. This prompted us to investigate the antiproliferative profile of a tachykinin-peptide from the Octopus kaurna, Octpep-1 in melanoma. We evaluated the cytotoxicity of Octpep-1 by MTT assay. Mechanistic insights on viability and cellular damage caused by Octpep-1 were gained via flow cytometry and bioenergetics. Structural and pharmacological characterization was conducted by molecular modelling, molecular biology, CRISPR/Cas9 technology, high-throughput mRNA and calcium flux analysis. In vivo efficacy was validated in two independent xerograph animal models (mice and zebrafish). Octpep-1 selectively reduced the proliferative capacity of human melanoma BRAFV600E -mutated cells with minimal effects on fibroblasts. In melanoma-treated cells, Octpep-1 increased ROS with unaltered mitochondrial membrane potential and promoted non-mitochondrial and mitochondrial respiration with inefficient ATP coupling. Molecular modelling revealed that the cytotoxicity of Octpep-1 depends upon the α-helix and polyproline conformation in the C-terminal region of the peptide. A truncated form of the C-terminal end of Octpep-1 displayed enhanced potency and efficacy against melanoma. Octpep-1 reduced the progression of tumours in xenograft melanoma mice and zebrafish. We unravel the intrinsic anti-tumoural properties of a tachykinin peptide. This peptide mediates the selective cytotoxicity in BRAF-mutated melanoma in vitro and prevents tumour progression in vivo, providing a foundation for a therapy against melanoma.

Treatment of non-functioning pituitary adenoma with cabergoline: a systematic review and meta-analysis.

To make a systematic review and meta-analysis of studies evaluating the effect of cabergoline (CBG) in the treatment of non-functioning pituitary adenomas (NFPAs). The primary outcome was tumor shrinkage, using as cut-off a reduction of at least 20% of the NFPA size from baseline. The secondary outcomes were prevention of tumor progression, clinically required additional interventions and adverse events (AE). Search strategies were applied to MEDLINE, EMBASE, LILACS and CENTRAL. Independent reviewers assessed the study eligibility, extracted data, and evaluated risk of bias. Random meta-analysis for the proportion of tumor shrinkage, prevention of tumor progression, clinically required additional interventions and frequency of AE were conducted. Five studies were included. The meta-analysis of proportion was 19% for tumor shrinkage (95% CI 8-38%, 4 studies, 108 participants), 50% for prevention of tumor progression (95% CI 35-64%, 5 studies, 187 participants), 14% for clinically required additional interventions (95% CI 6-30%, 4 studies, 128 participants) and 2% for adverse events (95% CI 1-6%, 3 studies, 157 participants). Effect of CBG to promote tumor shrinkage in NFPAs was low, while prevention of tumor progression after surgery was seen in half of the cases, with a low frequency of adverse events. PROSPERO CRD42020206778.

Arsenic trioxide inhibits angiogenesis of hepatocellular carcinoma after insufficient radiofrequency ablation via blocking paracrine angiopoietin-1 and angiopoietin-2

Objectives Angiogenesis occurs during tumor progression of hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (RFA). Arsenic trioxide (ATO) shows promising therapeutic potential in advanced HCC. Whether ATO regulates angiogenesis and can be used to prevent tumor progression in HCC after insufficient RFA is still unknown. Methods Insufficient RFA was simulated using a water bath. MTT assay and tube formation assay were used to evaluate the effects of ATO on viability and proangiogenic abilities of SMMC7721 and HepG2 cells after insufficient RFA in vitro. The molecular changes with the treatment of ATO were evaluated through Western blot. An ectopic nude mice model was used to evaluate the effect of ATO on the tumor of SMMC7721 cells in vivo after insufficient RFA. Results In this study, HepG2 and SMMC7721 cells after insufficient RFA (named HepG2-H and SMMC7721-H, respectively) showed higher proliferation than the untreated cells and promoted tube formation of endothelial cells in a paracrine manner. ATO eliminated the difference in proliferation between untreated and RFA-treated cells and suppressed angiogenesis induced by HCC cells after insufficient RFA through the Ang-1 (angiopoietin-1)/Ang-2 (angiopoietin-2)/Tie2 pathway. Hif-1α overexpression abolished the inhibitory effect of ATO on angiogenesis in HCC after insufficient RFA. ATO inhibited tumor growth and angiogenesis in HCC after insufficient RFA. Conclusions Our results demonstrate that ATO blocks the paracrine signaling of Ang-1 and Ang-2 by inhibiting p-Akt/Hif-1α and further suppresses the angiogenesis of HCC after insufficient RFA.

Fibroblast activation protein (FAP) expression in CK5/6 expressed (Basal subtype) & CK20 expressed (Luminal subtype) urothelial bladder carcinoma: an immunohistochemical study

ABSTRACT Urinary bladder cancer incidence varies all over the world. Egypt displays high incidence rates. Molecular subtyping helps risk stratification and personalized treatment. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment may provoke tumor-promotion or tumor suppression. Fibroblast activation protein (FAP) is a marker of CAFs, suggested to accelerate tumor progression in various cancers. In urothelial carcinoma, investigations regarding impact of FAP expression on prognosis are needed. This work aims to study impact of FAP expression in urothelial carcinoma and find its relation to CK 5/6 (basal) expressed and CK 20 (luminal) expressed immunohistochemical markers. This retrospective study included 70 urothelial carcinoma specimens. Immunohistochemistry was performed and results were analyzed. FAP was expressed in 67.1% of cases and showed significant association with advanced tumor stage, muscle invasion, mitoses in tumor cells and stratified groups; as 73.9% of FAP positive cases were of Ck5/6+/Ck20- (basal subtype). All studied parameters did not show significant association with patient’s overall survival. In conclusion, FAP could have a role in modulating tumor microenvironment and promoting tumor invasion. FAP is correlated with basal subtype of urothelial carcinoma, which may be an indicator of tumor aggressiveness. FAP antagonists may be helpful in preventing tumor progression.

S100A14: A novel negative regulator of cancer stemness and immune evasion by inhibiting STAT3-mediated programmed death-ligand 1 expression in colorectal cancer.

BackgroundProgrammed death‐ligand 1 (PD‐L1) has functional roles in cancer stem‐like cell (CSC) phenotypes and chemoresistance besides immune evasion. Chemotherapy is a common treatment choice for colorectal cancer (CRC) patients; however, chemoresistance limits its effectiveness of treatment.MethodsWe examined the role of S100A14 (SA14) in CRC by adopting PD‐L1high subpopulations within CRC cell lines and patient tumours, by establishing PD‐L1high chemoresistant CRC sublines through prolonged exposure to 5‐fluorouracil/oxaliplatin‐based chemotherapy in vitro and in vivo, and by analysing a public database.ResultsWe identified a novel function of SA14 as a regulator of immune surveillance, major CSC phenotypes, and survival capacity under hostile microenvironments, including those harbouring chemotherapeutics, and as a prognostic biomarker in CRC. Mechanistically, SA14 inhibits PD‐L1 expression by directly interacting with signal transducer and activator of transcription 3 (STAT3) and inducing its proteasome‐mediated degradation. While gain‐of‐SA14 causes loss of PD‐L1 expression and tumourigenic potential and sensitisation to chemotherapy‐induced apoptosis in chemoresistant CRC cells, loss‐of‐SA14 causes increases in PD‐L1 expression, tumourigenic potential, and chemoresistance in vitro and in vivo. We further show that a combinatorial treatment with chemotherapy and recombinant SA14 protein effectively induces apoptosis in PD‐L1high chemoresistant CRC cells.ConclusionsOur results suggest that SA14‐based therapy is an effective strategy to prevent tumour progression and that SA14 is a predictive biomarker for anti‐PD‐L1 immunotherapy and chemotherapy in combination.

Abstract 5990: Targeted nanoparticles reduce tumor progression and lung metastasis by limiting DNA damage repair and immune suppression in metastatic triple-negative breast cancer

Abstract Background: Metastatic triple-negative breast cancer (TNBC), especially with BRCA1/2 mutations, is a deadly subtype of breast cancer with ~12% of 5-year survival. Despite their FDA approval, the therapeutic benefits of poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) are limited to BRCA1/2 mutated malignancies. Moreover, the PARPi olaparib has been shown to upregulate the expression of programmed death-ligand 1 (PD-L1) leading to immune suppression. The purpose of this study is to investigate if a novel nanoparticle formulation of oligomer hyaluronic acid (oHA) and doxorubicin (DOX) co-loaded in an iRGD-conjugated polymer-lipid nanocarrier (iRGD-DOX-oHA-PLN) can inhibit DNA damage repair and suppress PD-L1 in both mutant and non-mutant TNBC cells and reduce tumor progression and lung metastasis compared to the PARPi olaparib. We postulate that the co-administered oHA will block the signaling pathways of native hyaluronic acid (HA) receptors, the cluster of differentiation 44 (CD 44) and receptor for HA mediated motility (RHAMM), that regulate DNA damage repair and immunosuppression and enhance DOX efficacy. Methods: In vitro cellular uptake of various DOX formulations by TNBC MDA-MB-231-luc-D3H2LN cells and MDA-MB-436 (BRCA1 mutant) cells was examined using confocal laser scanning microscopy or spectrophotometer. The expression level of RHAMM, PD-L1, and PARP1 parylation (PAR) was evaluated after treatment with iRGD-DOX-oHA-PLN or olaparib in both cell lines using western blot or confocal laser scanning microscopy. The therapeutic efficacy of iRGD-DOX-oHA-PLN compared to olaparib was determined by monitoring the tumor progression and lung metastasis development in orthotopic breast tumor models of MDA-MB-231-luc-D3H2LN or MDA-MB-436 cell line. Results: The expression of native HA receptor RHAMM was profoundly reduced by ~5 folds in vivo and the DNA DSB was significantly increased by the iRGD-DOX-oHA-PLN treatment with 40% of γH2AX positive cells in tumor tissue sections. The iRGD-functionalized PLN enhanced DOX cellular uptake compared to DOX free drug or non-targeted NPs by ~3- and ~1.5-fold, in MDA-MB-231 and MDA-MB-436 cells, respectively. While olaparib upregulated PD-L1 and free DOX increased PAR level, the iRGD-DOX-oHA-PLN reduced the parylation and PD-L1 expression in both TNBC cell lines. The iRGD-DOX-oHA-PLN treatment (two dose of 10 mg/kg i.v. biweekly) outperformed olaparib (twenty doses of 50 mg/kg i.p 5x/week) in preventing tumor progression and lung metastasis in vivo over a 4-week period. Conclusion: The results suggest that the iRGD-DOX-oHA-PLN can effectively inhibit DNA damage repair and immunosuppression of cancer cells and could be a promising multitargeted nanomedicine for the treatment of both BRCA1-mutant and non-mutant metastatic TNBC. Citation Format: Ibrahim Alradwan, Pei Zhi, Tian Zhang, HoYin Lip, Abdulmutalib Zetrini, Chunsheng He, Jeffery Henderson, Andrew Rauth, Xiao Yu Wu. Targeted nanoparticles reduce tumor progression and lung metastasis by limiting DNA damage repair and immune suppression in metastatic triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5990.

Piceatannol Prevents Colon Cancer Progression via Dual-Targeting to M2-Polarized Tumor-Associated Macrophages and the TGF-β1 Positive Feedback Signaling Pathway.

M2 phenotype tumor-associated macrophages (M2-TAMs) play a key role in distant metastasis and poor clinical outcomes. Herein, a specific molecular mechanism that contributes to malignant progression is illuminated and investigates whether piceatannol (PIC) can target the crosstalk between M2-TAMs and cancer cells for potential colorectal cancer (CRC) therapy. To mimic the tumor microenvironment (TME), direct and indirect coculture systems in vitro and in vivo mouse xenograft models are established. The results demonstrate that post-treatment with PIC in TME more effectively prevented the aggressive features and stemness of SW480 cells by restricting the polarization of M2-like macrophages and blocking the transforming growth factor β1 (TGF-β1) positive feedback autocrine/paracrine loop that exists between M2-like polarized macrophages and cancer cells. Furthermore, xenograft assays also observe significant repression in tumor growth and lung metastases with the administration of PIC. The key mechanism underlying the antimetastasis effects of PIC may include its directly inhibitory activity against TGF-β receptor type-1 (TGF-βR1) in the M2-like TAMs-created TME. These novel findings demonstrate that PIC is a potent TGF-β1/TGF-βR1 pathway inhibitor and TME modulator for preventing tumor progression and metastasis in CRC by reeducating TAMs.

Abstract 2520: Ovarian tumors escape anti-tumor function of NK cells by inducing CISH expression and its inhibition prevents tumor progression

Abstract Background: Ovarian cancer (OVCA), a lethal malignancy of women, mainly disseminates locally in the peritoneal cavity and the local immune system plays important roles in inhibiting its progression. Although NK cells, a member of innate immunity, recognize and exert anti-tumor immune responses, tumors escape NK cell immunity and progress to late stages by inducing factors like inhibitory receptors and cytokines. IL-15, a cytokine, stimulates NK cell function and persistent exposure to IL-15 induces cytokine inducible SH2-containing protein (CISH), an inhibitory receptor and a marker of NK cell exhaustion. It is unknown if ovarian tumors use this phenomenon in their favor as the tumor secretes enhanced levels of IL-15. Furthermore, dietary supplementation with root powder of Ashwagandha (ASH), a natural herb and an anti-stress compound has shown to decrease the rates of OVCA metastasis and enhance the frequency of intratumoral NK cells in a preclinical model. However, it is unknown if ASH supplementation improves NK cell frequency by inhibiting CISH. The goal of this study was to examine if OVCA progresses by inducing CISH-expression in NK cells and if dietary ASH supplementation reduces NK cell exhaustion by decreasing CISH expression. Materials and methods: Two studies were conducted. Study 1: Exploratory study with clinical specimens including normal ovaries (n=5) and ovarian high grade serous carcinoma at early and late stages (n=5 each). Study 2: Prospective study using the laying hen model of OVCA supplemented with or without 2% dietary ASH root powder for 90 days (n=7 for each group; normal, early and late stage). Hen normal and tumor ovarian tissues were collected at the end of the study. Both the clinical and hen specimens were used for immunohistochemistry, Western blotting and gene expression assays to determine the frequency of CISH-expressing NK-cells and intensity of GRP78 expression (a marker of cellular stress). Data were collected and analyzed by ANOVA and unpaired t-test and considered significant when P<0.05. Results: CISH-expressing NK cells were localized in normal and tumor ovaries in women and hens. Compared with normal ovaries, frequency of CISH-expressing NK cells was significantly higher in tumors at early and late stages in patients and hens. Similarly, strong expression of CISH gene and protein (29kDa) was detected in tumor tissues. Enhanced expression of CISH positively correlated with expression of GRP78. Compared with untreated, ASH supplementation reduced tumor progression in 5 out of 7 hens and significantly decreased the frequency of CISH-expressing NK cells and GRP78 (P<0.001). Conclusion: The results of this study suggest that expression of CISH by NK cells and cellular stress were associated with OVCA progression and dietary ASH supplementation reduced NK cell exhaustion by decreasing CISH and GRP78. Support: Swim Across America and NIH CA187309 Citation Format: Jasmin C. Acosta, Amy K. Stasik, Janice M. Bahr, Animesh Barua. Ovarian tumors escape anti-tumor function of NK cells by inducing CISH expression and its inhibition prevents tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2520.

Heparan sulfate dependent binding of plasmatic von Willebrand factor to blood circulating melanoma cells attenuates metastasis

Heparan sulfate (HS), a highly negatively charged glycosaminoglycan, is ubiquitously present in all tissues and also exposed on the surface of mammalian cells. A plethora of molecules such as growth factors, cytokines or coagulation factors bear HS binding sites. Accordingly, HS controls the communication of cells with their environment and therefore numerous physiological and pathophysiological processes such as cell adhesion, migration, and cancer cell metastasis. In the present work, we found that HS exposed by blood circulating melanoma cells recruited considerable amounts of plasmatic von Willebrand factor (vWF) to the cellular surface. Analyses assisted by super-resolution microscopy indicated that HS and vWF formed a tight molecular complex. Enzymatic removal of HS or genetic engineering of the HS biosynthesis showed that a reduced length of the HS chains or complete lack of HS was associated with significantly reduced vWF encapsulation. In microfluidic experiments, mimicking a tumor-activated vascular system, we found that vWF-HS complexes prevented vascular adhesion. In line with this, single molecular force spectroscopy suggested that the vWF-HS complex promoted the repulsion of circulating cancer cells from the blood vessel wall to counteract metastasis. Experiments in wild type and vWF knockout mice confirmed that the HS-vWF complex at the melanoma cell surface attenuated hematogenous metastasis, whereas melanoma cells lacking HS evade the anti-metastatic recognition by vWF. Analysis of tissue samples obtained from melanoma patients validated that metastatic melanoma cells produce less HS. Transcriptome data further suggest that attenuated expression of HS-related genes correlate with metastases and reduced patients’ survival. In conclusion, we showed that HS-mediated binding of plasmatic vWF to the cellular surface can reduce the hematogenous spread of melanoma. Cancer cells with low HS levels evade vWF recognition and are thus prone to form metastases. Therefore, therapeutic expansion of the cancer cell exposed HS may prevent tumor progression.

Antitumor Potential of Immunomodulatory Natural Products.

Cancer is one of the leading causes of death globally. Anticancer drugs aim to block tumor growth by killing cancerous cells in order to prevent tumor progression and metastasis. Efficient anticancer drugs should also minimize general toxicity towards organs and healthy cells. Tumor growth can also be successfully restrained by targeting and modulating immune response. Cancer immunotherapy is assuming a growing relevance in the fight against cancer and has recently aroused much interest for its wider safety and the capability to complement conventional chemotherapeutic approaches. Natural products are a traditional source of molecules with relevant potential in the pharmacological field. The huge structural diversity of metabolites with low molecular weight (small molecules) from terrestrial and marine organisms has provided lead compounds for the discovery of many modern anticancer drugs. Many natural products combine chemo-protective and immunomodulant activity, thus offering the potential to be used alone or in association with conventional cancer therapy. In this review, we report the natural products known to possess antitumor properties by interaction with immune system, as well as discuss the possible immunomodulatory mechanisms of these molecules.

Hypoxia Selectively Increases a SMAD3 Signaling Axis to Promote Cancer Cell Invasion.

Simple SummaryWhile 90% of cancer patient deaths are caused by cancer dissemination through metastasis, no current therapy selectively targets this process due to the lack of selective inhibitors. Various intratumoral factors are known to promote metastasis, notably low oxygen concentration, called hypoxia, and various growth factors, including transforming growth factor β (TGFβ). Our group previously demonstrated that hypoxia enhances TGFβ-induced cancer cell invasion processes. The present study further characterizes the mechanisms involved in hypoxia-induced cancer cell invasion using in vitro, in vivo and in silico approaches and identifies a HDAC6- SMAD3 pathway that can be pharmacologically targeted to inhibit tumor progression.Transforming growth factor β (TGFβ) plays a paradoxical role in cancer, first inhibiting then promoting its progression, a duality that poses a real challenge for the development of effective TGFβ-targeted therapies. The major TGFβ downstream effectors, SMAD2 and SMAD3, display both distinct and overlapping functions and accumulating evidence suggests that their activation ratio may contribute to the dual effect of TGFβ. However, the mechanisms responsible for their selective activation remain poorly understood. Here, we provide experimental evidence that hypoxia induces the pro-invasive arm of TGFβ signaling through a selective increase in SMAD3 interaction with SMAD-Anchor for Receptor Activation (SARA). This event relies on HDAC6-dependent SMAD3 bioavailability, as well as increased SARA recruitment to EEA1+ endosomes. A motility gene expression study indicated that SMAD3 selectively increased the expression of ITGB2 and VIM, two genes that were found to be implicated in hypoxia-induced cell invasion and associated with tumor progression and metastasis in cohorts of cancer patients. Furthermore, CAM xenograft assays show the significant benefit of selective inhibition of the SMAD3 signaling pathway as opposed to global TGFβ inhibition in preventing tumor progression. Overall, these results suggest that fine-tuning of the pro-invasive HDAC6-SARA-SMAD3 axis could be a better strategy towards effective cancer treatments.

Bridging treatment prior to liver transplantation for hepatocellular carcinoma: radioembolization or transarterial chemoembolization?

BackgroundIn hepatocellular carcinoma (HCC) patients, intraarterial therapies are regularly employed as a bridge to liver transplantation to prevent tumor progression during waiting time. Objective of this study was to compare HCC recurrence after liver transplantation following TACE or radioembolization bridging treatment.MethodsWe retrospectively analyzed prospectively collected data on 131 consecutive HCC patients who underwent liver transplantation between January 2007 and December 2017 at our liver transplant center (radioembolization n = 44, TACE n = 87). Multivariable logistic regression and cox proportional hazard regression models were used to evaluate factors associated with tumor recurrence and post-transplant survival.ResultsBetween groups, patients were comparable with regards to age and gender. In the radioembolization group, Milan criteria for HCC were met significantly less frequently (20.5% vs. 65.5%, p < 0.0001). Patients in the radioembolization group required significantly fewer intraarterial treatments (1 [1–2] vs. 1 [1–7], p = 0.0007). On explant specimen, tumor differentiation, microvascular invasion and tumor necrosis were comparable between the groups. HCC recurrence and overall survival were similar between the groups. Multivariable analysis detected increasing recipient age, male gender, complete tumor necrosis and absence of microvascular invasion being independently associated with decreased odds for HCC recurrence. Increasing model of end-stage liver disease (MELD) score and tumor recurrence were independently associated with increased odds of post-transplant death.ConclusionsIntraarterial bridging treatment leading to tumor necrosis may not only prevent waitlist drop-out but also facilitate long-term successful liver transplantation in HCC patients. Both radioembolization and TACE represent potent treatment strategies.

When PIP2 Meets p53: Nuclear Phosphoinositide Signaling in the DNA Damage Response.

The mechanisms that maintain genome stability are critical for preventing tumor progression. In the past decades, many strategies were developed for cancer treatment to disrupt the DNA repair machinery or alter repair pathway selection. Evidence indicates that alterations in nuclear phosphoinositide lipids occur rapidly in response to genotoxic stresses. This implies that nuclear phosphoinositides are an upstream element involved in DNA damage signaling. Phosphoinositides constitute a new signaling interface for DNA repair pathway selection and hence a new opportunity for developing cancer treatment strategies. However, our understanding of the underlying mechanisms by which nuclear phosphoinositides regulate DNA damage repair, and particularly the dynamics of those processes, is rather limited. This is partly because there are a limited number of techniques that can monitor changes in the location and/or abundance of nuclear phosphoinositide lipids in real time and in live cells. This review summarizes our current knowledge regarding the roles of nuclear phosphoinositides in DNA damage response with an emphasis on the dynamics of these processes. Based upon recent findings, there is a novel model for p53’s role with nuclear phosphoinositides in DNA damage response that provides new targets for synthetic lethality of tumors.

A Critical Overview of Targeted Therapies for Vestibular Schwannoma.

Vestibular schwannoma (VS) is a benign tumor that originates from Schwann cells in the vestibular component. Surgical treatment for VS has gradually declined over the past few decades, especially for small tumors. Gamma knife radiosurgery has become an accepted treatment for VS, with a high rate of tumor control. For neurofibromatosis type 2 (NF2)-associated VS resistant to radiotherapy, vascular endothelial growth factor (VEGF)-A/VEGF receptor (VEGFR)-targeted therapy (e.g., bevacizumab) may become the first-line therapy. Recently, a clinical trial using a VEGFR1/2 peptide vaccine was also conducted in patients with progressive NF2-associated schwannomas, which was the first immunotherapeutic approach for NF2 patients. Targeted therapies for the gene product of SH3PXD2A-HTRA1 fusion may be effective for sporadic VS. Several protein kinase inhibitors could be supportive to prevent tumor progression because merlin inhibits signaling by tyrosine receptor kinases and the activation of downstream pathways, including the Ras/Raf/MEK/ERK and PI3K/Akt/mTORC1 pathways. Tumor-microenvironment-targeted therapy may be supportive for the mainstays of management. The tumor-associated macrophage is the major component of immunosuppressive cells in schwannomas. Here, we present a critical overview of targeted therapies for VS. Multimodal therapy is required to manage patients with refractory VS.

Long Noncoding RNA HCP5 Contributes to Nasopharyngeal Carcinoma Progression by Targeting MicroRNA-128-3p.

Aim To determine the role and underlying mechanism of lncRNA HCP5 in nasopharyngeal carcinoma (NPC). Method The expression of HCP5 and miR-128-3p was assessed by qRT-PCR. CCK-8, EdU staining, and transwell were performed to determine cell progression. A nude mouse xenograft tumor model was carried out to detect the role of HCP5 in vivo. The luciferase assay was performed to confirm the function between lncRNA HCP5 and miR-128-3p. Results The increased level of HCP5 was observed in NPC tissues. Silencing of HCP5 prevented tumor progression in vitro and in vivo. The luciferase assay verified that HCP5 could bind with miR-128-3p. Furthermore, forced expression of miR-128-3p could prevent the function of HCP5 on NPC cells. Conclusion lncRNA HCP5 could regulate NPC cell progression via sponging miR-128-3p, which might serve as a potential therapy target of NPC.

Assembly and localization of extracellular matrix protein fibronectin modulates Natural killer cell infiltration in tumor spheroids.

Abstract Natural Killer cells (NK), the major innate effector cells, with their broad cytotoxicity against tumors are ideal candidates for immunotherapy. Once having entered the malignant site, NK cells encounter a complex environment composed of tumor cells, non-tumor cells along with the extra cellular matrix (ECM). As one of the integral components of the tumor microenvironment (TME), the normal regulation of the extra cellular matrix (ECM) is necessary to prevent tumor progression and metastasis. Nevertheless, the impact of the matrix architecture found in solid tumors on immune cells and especially NK cells is not well characterized. Here we investigated the role of Fibronectin, a fibrous ECM protein, and its assembly and localization on NK cell infiltration into clear cell renal cell carcinoma (ccRCC) spheroids. 3D tumor spheroids established from the ccRCC cell line 786-O (RCC-) that lacks the Von Hippel-Lindau (VHL) gene are incapable of fibronectin assembly in their ECM. However, addition of the VHL gene into the 786-O cells (RCC+) reversed this phenotype facilitating fibronectin assembly. Fibronectin in RCC-spheroids exhibited prominent peripheral localization in contrast to RCC+ spheroids where fibronectin was detected towards the center of the spheroid. Coincident with fibronectin localization, PKH26 labeled Natural killer cell line, NKL, showed significantly increased infiltration into RCC+ spheroids compared to RCC-spheroids that lacked the tumor suppressor VHL. Thus, assembly and localization of fibronectin modulates NK cell infiltration in RCC tumors. Supported by grants from NIH U54MD012388 (NR and AV) and NIH U54CA143925 (NACP-NAU) to NR.

Multi-targeting of K-Ras domains and mutations by peptide and small molecule inhibitors.

K-Ras activating mutations are significantly associated with tumor progression and aggressive metastatic behavior in various human cancers including pancreatic cancer. So far, despite a large number of concerted efforts, targeting of mutant-type K-Ras has not been successful. In this regard, we aimed to target this oncogene by a combinational approach consisting of small peptide and small molecule inhibitors. Based on a comprehensive analysis of structural and physicochemical properties of predominantly K-Ras mutants, an anti-cancer peptide library and a small molecule library were screened to simultaneously target oncogenic mutations and functional domains of mutant-type K-Ras located in the P-loop, switch I, and switch II regions. The selected peptide and small molecule showed notable binding affinities to their corresponding binding sites, and hindered the growth of tumor cells carrying K-RasG12D and K-RasG12C mutations. Of note, the expression of K-Ras downstream genes (i.e., CTNNB1, CCND1) was diminished in the treated Kras-positive cells. In conclusion, our combinational platform signifies a new potential for blockade of oncogenic K-Ras and thereby prevention of tumor progression and metastasis. However, further validations are still required regarding the in vitro and in vivo efficacy and safety of this approach.

Dahuang Fuzi Baijiang decoction restricts progenitor to terminally exhausted T cell differentiation in colorectal cancer.

Obesity increases the risk of colorectal cancer (CRC) by 30%. The obese tumor microenvironment compromises antitumor immunity by eliciting exhausted T cells (Tex). Hypothesizing that Dahuang Fuzi Baijiang decoction (DFB) is a combined classical prescription from the “Synopsis of Prescriptions of the Golden Chamber”. We first determined that DFB regresses tumor growth in high‐fat diet–induced obese mice by expanding the TIM3− subset with intermediate expression of programmed cell death‐1 (PD‐1intTIM3−) and restricting the PD‐1hiTIM3+ subset. Transcription factor 1 (TCF1) is highly expressed in the PD‐1intTIM3− subset but is absent in PD‐1hiTIM3+ cells. We next confirmed that progenitor PD‐1intTCF+ cells robustly produce tumor necrosis factor‐α (TNFα) and interferon‐γ, whereas terminally differentiated PD‐1intTCF+ cells have defects in generating TNFα. With transgenic ob/ob mice, we found that DFB produces cooperative efficacy with anti‐PD‐1 (αPD‐1) by limiting the PD‐1hiTim3+ subset and amplifying the PD‐1intTCF+ population. Finally, we defined the recombinant chemokine C‐C‐motif receptor 2 (CCR2)+CD8+ subset as terminal Tex and identified that the differentiation from progenitor to terminal Tex is driven, at least in part, by the chemokine (C‐C motif) ligand 2 (CCL2)/CCR2 axis. The CCR2 inhibitor enhances the response to αPD‐1 by promoting the counts of progenitor Tex. Altogether, DFB dampens CCL2 and preserves progenitor Tex in the obese microenvironment to restrain CRC progression. These findings provide unambiguous evidence that the traditional Chinese formula DFB can prevent tumor progression by modulating adaptive immunity and establish a strong rationale for further clinical verification.

187P Development of a magnetic nanostructure for co-delivery of metformin and silibinin on growth of lung cancer cells: Possible action through leptin gene and its receptor regulation

Chemotherapeutic combinational approaches would be more efficient in decreasing toxicity of drug, preventing tumor progression in relation to either drug alone. Hence, the aim of this study was to construct magnetic PLGA/PEG nanoparticles (NPs) co-loaded with metformin (Met) and silibinin (Sil) to investigate their cytotoxicity as well as their impact on mRNA expression levels of leptin and leptin receptor genes in A549 lung cancer cells.

Hibiscus Sabdariffa L. Nanoparticles Offer a Preventive Potential Against Experimental Ehrlich Solid Carcinoma

Hibiscus sabdariffa L. has been widely cultivated in tropical areas, usually used in treatment of many disorders. Thus, in our study we aimed to evaluate the effect of dairy desserts supplemented with nanoform of Hibiscus sabdariffa L. extract (NHSE) against Ehrlich solid carcinoma (ESC) in mice. The NHSE was prepared by soaked the fine powder of plant in 90% ethanol by cold extraction. NHSE was evaluated using dynamic light scattering (DLS) and transmission electron microscope (TEM), then the prepared NHSE was added to dairy desserts using different concentrations. Sixty female albino mice were used and divided into six groups. After the end of the experimental period, blood was withdrawn; Serum was separated for determination of malondialdehyde (MDA), super oxidedismutase (SOD), catalase (CAT), tumor necrosis factor- α (TNF-α), matrix metalloproteinases-9 (MMP-9) and B-cell lymphoma-2 (Bcl-2). Serum homocystein (Hcy) level was estimated by high performance liquid chromatography (HPLC). Mice inoculated intramuscularly with Ehrlich cell line showed statistically marked increase in serum levels of MDA, TNF-α, MMP-9 and Hcy accompanied by marked decrease in SOD and CAT activities and Bcl-2 levels compared to the control group. Treatments with NHSE markedly trigger activity of anti-oxidant, attenuated the inflammatory response, reduced levels of Hcy and stimulated the apoptosis of tumor cells. Based on that, dairy desserts containing NHSE showed effective role in prohibiting the releasing of reactive oxygen species, ameliorating the immune response, and preventing tumor progression.